U.S. patent application number 10/126113 was filed with the patent office on 2003-01-09 for therapeutic use of selective pde10 inhibitors.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Lebel, Lorraine A., Menniti, Frank S., Schmidt, Christopher J..
Application Number | 20030008806 10/126113 |
Document ID | / |
Family ID | 23092939 |
Filed Date | 2003-01-09 |
United States Patent
Application |
20030008806 |
Kind Code |
A1 |
Lebel, Lorraine A. ; et
al. |
January 9, 2003 |
Therapeutic use of selective PDE10 inhibitors
Abstract
The invention provides a method for treating certain neurologic
and psychiatric disorders in mammals, including humans, comprising
administration of a selective PDE10 inhbitor. In particular, the
invention relates to treatment of mood, movement, and anxiety
disorders; psychosis; drug, for example alcohol, addiction; and
disorders having as a symptom deficient cognition. The invention
furthermore provides the use of papaverine as a selective inhibitor
of PDE10.
Inventors: |
Lebel, Lorraine A.; (North
Stonington, CT) ; Menniti, Frank S.; (Mystic, CT)
; Schmidt, Christopher J.; (Old Lyme, CT) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
23092939 |
Appl. No.: |
10/126113 |
Filed: |
April 19, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60285148 |
Apr 20, 2001 |
|
|
|
Current U.S.
Class: |
514/1 |
Current CPC
Class: |
A61P 25/32 20180101;
A61P 43/00 20180101; A61P 25/14 20180101; G01N 2800/301 20130101;
A61P 25/30 20180101; G01N 2800/302 20130101; G01N 33/6896 20130101;
A61P 25/16 20180101; A61P 25/28 20180101; A61P 25/00 20180101; A61K
31/472 20130101; A61P 25/18 20180101; A61P 25/24 20180101; G01N
2500/10 20130101; A61K 31/00 20130101; A61P 25/36 20180101; A61P
25/22 20180101 |
Class at
Publication: |
514/1 |
International
Class: |
A61K 031/00 |
Claims
1. A method of treating an anxiety or psychotic disorder in a
mammal which comprises administering to said mammal an amount of a
selective PDE10 inhibitor effective in treating said anxiety or
psychotic disorder.
2. A method according to claim 1, wherein the psychotic disorder is
selected from schizophrenia, for example of the paranoid,
disorganized, catatonic, undifferentiated, or residual type;
schizophreniform disorder; schizoaffective disorder, for example of
the delusional type or the depressive type; delusional disorder;
substance-induced psychotic disorder, for example psychosis induced
by alcohol, amphetamine, cannabis, cocaine, hallucinogens,
inhalants, opioids, or phencyclidine; personality disorder of the
paranoid type; and personality disorder of the schizoid type; and
the anxiety disorder is selected from panic disorder; agoraphobia;
a specific phobia; social phobia; obsessive-compulsive disorder;
post-traumatic stress disorder; acute stress disorder; and
generalized anxiety disorder.
3. A method of treating a movement disorder selected from
Huntington's disease and dyskinesia associated with dopamine
agonist therapy in a mammal, which method comprises administering
to said mammal an amount of a selective PDE10 inhibitor effective
in treating said disorder.
4. A method of treating a movement disorder selected from
Parkinson's disease and restless leg syndrome in a mammal
comprising administering to said mammal an amount of a selective
PDE10 inhibitor effective in treating said disorder.
5. A method of treating a drug addiction, for example an alcohol,
amphetamine, cocaine, or opiate addiction, in a mammal, which
method comprises administering to said mammal an amount of a
selective PDE10 inhibitor effective in treating drug addiction.
6. A method of treating a disorder comprising as a symptom a
deficiency in cognition in a mammal, which method comprises
administering to said mammal an amount of a selective PDE10
inhibitor effective in treating deficient cognition.
7. A method according to claim 6, wherein the disorder is selected
from dementia, for example Alzheimer's disease, multi-infarct
dementia, alcoholic dementia or other drug-related dementia,
dementia associated with intracranial tumors or cerebral trauma,
dementia associated with Huntington's disease or Parkinson's
disease, or AIDS-related dementia; delirium; amnestic disorder;
post-traumatic stress disorder; mental retardation; a learning
disorder, for example reading disorder, mathematics disorder, or a
disorder of written expression; attention-deficit/hyperactivity
disorder; and age-related cognitive decline.
8. A method of treating a mood disorder or mood episode in a mammal
comprising administering to said mammal an amount of a selective
PDE10 inhibitor effective in treating said disorder or episode.
9. A method according to claim 8, wherein the mood disorder or mood
episode is selected from a major depressive episode of the mild,
moderate or severe type, a manic or mixed mood episode, a hypomanic
mood episode; a depressive episode with a typical features; a
depressive episode with melancholic features; a depressive episode
with catatonic features; a mood episode with postpartum onset;
post-stroke depression; major depressive disorder; dysthymic
disorder; minor depressive disorder; premenstrual dysphoric
disorder; post-psychotic depressive disorder of schizophrenia; a
major depressive disorder superimposed on a psychotic disorder such
as delusional disorder or schizophrenia; a bipolar disorder, for
example bipolar I disorder, bipolar II disorder, and cyclothymic
disorder.
10. A method of treating an anxiety or psychotic disorder in a
mammal, which method comprises administering to said mammal an
amount of a selective PDE10 inhibitor effective in inhibiting
PDE10.
12. A method according to claim 10, wherein the psychotic disorder
is selected from schizophrenia, for example of the paranoid,
disorganized, catatonic, undifferentiated, or residual type;
schizophreniform disorder; schizoaffective disorder, for example of
the delusional type or the depressive type; delusional disorder;
substance-induced psychotic disorder, for example psychosis induced
by alcohol, amphetamine, cannabis, cocaine, hallucinogens,
inhalants, opioids, or phencyclidine; personality disorder of the
paranoid type; and personality disorder of the schizoid type; and
the anxiety disorder is selected from panic disorder; agoraphobia;
a specific phobia; social phobia; obsessive-compulsive disorder;
post-traumatic stress disorder; acute stress disorder; and
generalized anxiety disorder.
13. A method of treating a movement disorder selected from
Huntington's disease and dyskinesia associated with dopamine
agonist therapy in a mammal, which method comprises administering
to said mammal an amount of a selective PDE10 inhibitor effective
in inhibiting PDE10.
14. A method of treating a movement disorder selected from
Parkinson's disease and restless leg syndrome in a mammal
comprising administering to said mammal an amount of a selective
PDE10 inhibitor effective in inhibiting PDE10.
15. A method of treating a drug addiction, for example an alcohol,
amphetamine, cocaine, or opiate addiction, in a mammal, which
method comprises administering to said mammal an amount of a
selective PDE10 inhibitor effective in inhibiting PDE10.
16. A method of treating a disorder comprising as a symptom a
deficiency in cognition in a mammal, which method comprises
administering to said mammal an amount of a selective PDE10
inhibitor effective in inhibiting PDE10.
17. A method according to claim 16, wherein the disorder is
selected from dementia, for example Alzheimer's disease,
multi-infarct dementia, alcoholic dementia or other drug-related
dementia, dementia associated with intracranial tumors or cerebral
trauma, dementia associated with Huntington's disease or
Parkinson's disease, or AIDS-related dementia; delirium; amnestic
disorder; post-traumatic stress disorder; mental retardation; a
learning disorder, for example reading disorder, mathematics
disorder, or a disorder of written expression;
attention-deficit/hyperactivity disorder; and age-related cognitive
decline.
18. A method of treating a mood disorder or mood episode in a
mammal comprising administering to said mammal an amount of a
selective PDE10 inhibitor effective in inhibiting PDE10.
19. A method according to claim 18, wherein the mood disorder or
mood episode is selected from a major depressive episode of the
mild, moderate or severe type, a manic or mixed mood episode, a
hypomanic mood episode; a depressive episode with a typical
features; a depressive episode with melancholic features; a
depressive episode with catatonic features; a mood episode with
postpartum onset; post-stroke depression; major depressive
disorder; dysthymic disorder; minor depressive disorder;
premenstrual dysphoric disorder; post-psychotic depressive disorder
of schizophrenia; a major depressive disorder superimposed on a
psychotic disorder such as delusional disorder or schizophrenia; a
bipolar disorder, for example bipolar I disorder, bipolar II
disorder, and cyclothymic disorder.
20. A method of selectively inhibiting PDE10 in a mammal comprising
administering to said mammal papaverine in an amount effective in
inhibiting PDE10.
Description
[0001] This application claims priority under 35 U.S.C. 119(e) of
U.S. Application No. 60/285,148, filed Apr. 20, 2001.
BACKGROUND OF THE INVENTION
[0002] The subject invention relates to the treatment of disorders
of the central nervous system. More particularly, the invention
relates to treatment of neurologic and psychiatric disorders, for
example psychosis and disorders comprising deficient cognition as a
symptom. This invention also relates to PDE10 inhibition.
[0003] The cyclic nucleotides, cyclic-adenosine monophosphate
(cAMP) and cyclic-guanosine monophosphate (cGMP), function as
intracellular second messengers regulating a vast array of
intracellular processes including in neurons in the central nervous
system. cAMP is synthesized by a family of membrane bound enzymes,
the adenylyl cyclases. A broad range of serpin family receptors
regulates these enzymes through a coupling mechanism mediated by
heterotrimeric G-proteins. Increases in intracellular cAMP leads to
activation of cAMP-dependent protein kinases, which regulate the
activity of other signaling kinases, transcription factors, and
enzymes via their phosphorylation. Cyclic-AMP may also directly
affect the activity of cyclic nucleotide regulated ion channels,
phosphodiesterases, or guanine nucleotide exchange factors. Recent
studies also suggest that intracellular cAMP may function as a
precursor for the neuromodulator, adenosine, following its
transport out of the cell.
[0004] Guanylyl cyclase, which synthesizes cGMP, exists in membrane
bound and cytoplasmic forms. The membrane bound form is coupled to
G-protein linked receptors such as that for ANP (atrial naturetic
peptide) whereas soluble guanylyl cyclase is activated by nitric
oxide (Wang, X. and Robinson, P. J. Journal of Neurochemistry
68(2):443-456, 1997). Similar to cAMP, downstream mediators of cGMP
signaling in the central nervous system include cGMP-gated ion
channels, cGMP-regulated phosphodiesterases and cGMP-dependent
protein kinases. Given the important role of cyclic nucleotides in
signal transduction within the central nervous system, therapeutic
benefits may be derived from the use of compounds that affect the
regulation of cyclic nucleotide signaling.
[0005] A principal mechanism for regulating cyclic nucleotide
signaling is by phosphodiesterase-catalyzed cyclic nucleotide
catabolism. There are eleven known families of phosphodiesterases
(PDEs) encoded by 21 different genes. Each gene typically yields
multiple splice variants that further contribute to the isozyme
diversity. The PDE families are distinguished functionally based on
cyclic nucleotide substrate specificity, mechanism(s) of
regulation, and sensitivity to inhibitors. Furthermore, PDEs are
differentially expressed throughout the organism, including in the
central nervous system. As a result of these distinct enzymatic
activities and localization, different PDEs isozymes can serve
distinct physiological functions. Furthermore, compounds that can
selectively inhibit distinct PDE families or isozymes may offer
particular therapeutic effects, fewer side effects, or both.
[0006] PDE10 is identified as a unique family based on primary
amino acid sequence and distinct enzymatic activity. Homology
screening of EST databases revealed mouse PDE10A as the first
member of the PDE10 family of phosphodiesterases (Fujishige et al.,
J. Biol. Chem. 274:18438-18445, 1999; Loughney, K. et al., Gene
234:109-117, 1999). The murine homologue has also been cloned
(Soderling, S. et al., Proc. Natl. Acad. Sci. USA 96:7071-7076,
1999) and N-terminal splice variants of both the rat and human
genes have been identified (Kotera, J. et al., Biochem. Biophys.
Res. Comm. 261:551-557, 1999; Fujishige, K. et al., Eur. J.
Biochem. 266:1118-1127, 1999). There is a high degree of homology
across species. The mouse PDE10A1 is a 779 amino acid protein that
hydrolyzes both cAMP and cGMP to AMP and GMP, respectively. The
affinity of PDE10 for cAMP (K.sub.m=0.05 .mu.M) is higher than for
cGMP (K.sub.m=3 .mu.M). However, the approximately 5-fold greater
V.sub.max for cGMP over cAMP has lead to the suggestion that PDE10
is a unique cAMP-inhibited cGMPase (Fujishige et al., J. Biol.
Chem. 274:18438-18445, 1999).
[0007] PDE10 also is uniquely localized in mammals relative to
other PDE families. mRNA for PDE10 is highly expressed only in
testis and brain (Fujishige, K. et al., Eur J Biochem.
266:1118-1127, 1999; Soderling, S. et al., Proc. Natl. Acad. Sci.
96:7071-7076, 1999; Loughney, K. et al., Gene 234:109-117, 1999).
These initial studies indicated that within the brain PDE10
expression is highest in the striatum (caudate and putamen), n.
accumbens, and olfactory tubercle. More recently, a detailed
analysis has been made of the expression pattern of PDE10 mRNA in
rodent brain (Seeger, T. F. et al., Abst. Soc. Neurosci. 26:345.10,
2000).
SUMMARY OF THE INVENTION
[0008] The present invention provides a method of treating an
anxiety or psychotic disorder in a mammal, including a human, which
comprises administering to said mammal an amount of a selective
PDE10 inhibitor effective in treating said anxiety or psychotic
disorder.
[0009] The invention also provides a method of treating an anxiety
or psychotic disorder in a mammal, including a human, which
comprises administering to said mammal an amount of a selective
PDE10 inhibitor effective in inhibiting PDE10.
[0010] Examples of psychotic disorders that can be treated
according to the present invention include, but are not limited to,
schizophrenia, for example of the paranoid, disorganized,
catatonic, undifferentiated, or residual type; schizophreniform
disorder; schizoaffective disorder, for example of the delusional
type or the depressive type; delusional disorder; substance-induced
psychotic disorder, for example psychosis induced by alcohol,
amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids,
or phencyclidine; personality disorder of the paranoid type; and
personality disorder of the schizoid type.
[0011] Examples of anxiety disorders that can be treated according
to the present invention include, but are not limited to, panic
disorder; agoraphobia; a specific phobia; social phobia;
obsessive-compulsive disorder; post-traumatic stress disorder;
acute stress disorder; and generalized anxiety disorder.
[0012] This invention also provides a method of treating a movement
disorder selected from Huntington's disease and dyskinesia
associated with dopamine agonist therapy in a mammal, including a
human, which method comprises administering to said mammal an
amount of a selective PDE10 inhibitor effective in treating said
disorder.
[0013] This invention also provides a method of treating a movement
disorder selected from Huntington's disease and dyskinesia
associated with dopamine agonist therapy in a mammal, including a
human, which method comprises administering to said mammal an
amount of a selective PDE10 inhibitor effective in inhibiting
PDE10.
[0014] This invention further provides a method of treating a
movement disorder selected from Parkinson's disease and restless
leg syndrome in a mammal, including a human, comprising
administering to said mammal an amount of a selective PDE10
inhibitor effective in treating said disorder.
[0015] This invention also provides a method of treating a movement
disorder selected from Parkinson's disease and restless leg
syndrome in a mammal, including a human, comprising administering
to said mammal an amount of a selective PDE10 inhibitor effective
in inhibiting PDE10.
[0016] This invention further provides a method of treating a drug
addiction, for example an alcohol, amphetamine, cocaine, or opiate
addiction, in a mammal, including a human, which method comprises
administering to said mammal an amount of a selective PDE10
inhibitor effective in treating drug addiction.
[0017] This invention also provides a method of treating a drug
addiction, for example an alcohol, amphetamine, cocaine, or opiate
addiction, in a mammal, including a human, which method comprises
administering to said mammal an amount of a selective PDE10
inhibitor effective in inhibiting PDE10.
[0018] A "drug addiction", as used herein, means an abnormal desire
for a drug and is generally characterized by motivational
disturbances such a compulsion to take the desired drug and
episodes of intense drug craving.
[0019] This invention further provides a method of treating a
disorder comprising as a symptom a deficiency in cognition in a
mammal, including a human, which method comprises administering to
said mammal an amount of a selective PDE10 inhibitor effective in
treating a deficiency cognition.
[0020] This invention also provides a method of treating a disorder
comprising as a symptom a deficiency in cognition in a mammal,
including a human, which method comprises administering to said
mammal an amount of a selective PDE10 inhibitor effective in
inhibiting PDE10.
[0021] The phrase "deficiency in cognition" as used herein in
"disorder comprising as a symptom a deficiency in cognition" refers
to a subnormal functioning in one or more cognitive aspects such as
memory, intellect, or learning and logic ability, in a particular
individual relative to other individuals within the same general
age population. "Deficiency in cognition" also refers to a
reduction in any particular individual's functioning in one or more
cognitive aspects, for example as occurs in age-related cognitive
decline.
[0022] Examples of disorders that comprise as a symptom a
deficiency in cognition that can be treated according to the
present invention are dementia, for example Alzheimer's disease,
multi-infarct dementia, alcoholic dementia or other drug-related
dementia, dementia associated with intracranial tumors or cerebral
trauma, dementia associated with Huntington's disease or
Parkinson's disease, or AIDS-related dementia; delirium; amnestic
disorder; post-traumatic stress disorder; mental retardation; a
learning disorder, for example reading disorder, mathematics
disorder, or a disorder of written expression;
attention-deficit/hyperactivity disorder; and age-related cognitive
decline.
[0023] This invention also provides a method of treating a mood
disorder or mood episode in a mammal, including a human, comprising
administering to said mammal an amount of a selective PDE10
inhibitor effective in treating said disorder or episode.
[0024] This invention also provides a method of treating a mood
disorder or mood episode in a mammal, including a human, comprising
administering to said mammal an amount of a selective PDE10
inhibitor effective in inhibiting PDE10.
[0025] Examples of mood disorders and mood episodes that can be
treated according to the present invention include, but are not
limited to, major depressive episode of the mild, moderate or
severe type, a manic or mixed mood episode, a hypomanic mood
episode; a depressive episode with a typical features; a depressive
episode with melancholic features; a depressive episode with
catatonic features; a mood episode with postpartum onset;
post-stroke depression; major depressive disorder; dysthymic
disorder; minor depressive disorder; premenstrual dysphoric
disorder; post-psychotic depressive disorder of schizophrenia; a
major depressive disorder superimposed on a psychotic disorder such
as delusional disorder or schizophrenia; a bipolar disorder, for
example bipolar I disorder, bipolar II disorder, and cyclothymic
disorder.
[0026] As used herein, the term "selective PDE10 inhibitor" refers
to a substance, for example an organic molecule, that effectively
inhibits an enzyme from the PDE10 family to a greater extent than
any other PDE enzyme, particularly any enzyme from the PDE 1-9
families or any PDE11 enzyme. In one embodiment, a selective PDE10
inhibitor is a substance, for example organic molecule, having a
K.sub.i for inhibition of PDE10 that is less than or about
one-tenth the K.sub.i that the substance has for inhibition of any
other PDE enzyme. In other words, the substance inhibits PDE10
activity to the same degree at a concentration of about one-tenth
or less than the concentration required for any other PDE
enzyme.
[0027] In general, a substance is considered to effectively
inhibition PDE10 activity if it has an IC.sub.50 of less than or
about 10 .mu.M, preferably less than or about 0.1 .mu.M.
[0028] A "selective PDE10 inhibitor" can be identified, for
example, by comparing the ability of a substance to inhibit PDE10
activity to its ability to inhibit PDE enzymes from the other PDE
families. For example, a substance may be assayed for its ability
to inhibit PDE10 activity, as well as PDE1, PDE2, PDE3A, PDE4A,
PDE4B, PDE4C, PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9, and PDE11.
[0029] In one embodiment of the therapeutic methods of the
invention described above, the selective PDE10 inhibitor is
papaverine.
[0030] This invention also provides a method of selectively
inhibiting PDE10 in a mammal, including a human, comprising
administering to said mammal papaverine in an amount effective in
inhibiting PDE10.
[0031] The term "treating", as in "a method of treating a
disorder", refers to reversing, alleviating, or inhibiting the
progress of the disorder to which such term applies, or one or more
symptoms of the disorder. As used herein, the term also
encompasses, depending on the condition of the patient, preventing
the disorder, including preventing onset of the disorder or of any
symptoms associated therewith, as well as reducing the severity of
the disorder or any of its symptoms prior to onset. "Treating" as
used herein refers also to preventing a recurrence of a
disorder.
[0032] For example, "treating schizophrenia, or schizophreniform or
schizoaffective disorder" as used herein also encompasses treating
one or more symptoms (positive, negative, and other associated
features) of said disorders, for example treating, delusions and/or
hallucination associated therewith. Other examples of symptoms of
schizophrenia and schizophreniform and schizoaffecctive disorders
include disorganized speech, affective flattening, alogia,
anhedonia, inappropriate affect, dysphoric mood (in the form of,
for example, depression, anxiety or anger), and some indications of
cognitive dysfunction.
[0033] The term "mammal", as used herein, refers to any member of
the class "Mammalia", including, but not limited to, humans, dogs,
and cats.
BRIEF DESCRIPTION OF THE FIGURES
[0034] FIG. 1: The Figure is a bar graph showing catalepsy in
animals versus increasing dose of papaverine. The gray bars
represent a papaverine in combination with haloperidol and show the
potentiation of haloperidol-induced catalepsy by papaverine. The
black bars represent papaverine alone. These black bars show that
papaverine did not alone induce catalepsy at a dose of up to 32
mg/kg. More particularly, papaverine was administered at the
indicated doses either alone or with haloperidol (0.32 mg/kg) 30
min prior to testing. Each bar is the mean latency for six
similarly treated animals to remove both forepaws from an elevated
bar. Kruskall-Wallace analysis of variance was used to compare the
ranked latencies for papaverine alone versus plus haloperidol. Post
hoc analysis indicates that animals dosed with 3.2, 10, and 32
mg/kg papaverine plus haloperidol had significantly (**) longer
latencies than that of animals treated with haloperidol alone.
[0035] FIG. 2: The Figure is two bar graphs each showing the mean
.+-.SEM number of crossovers for animals in a shuttle box study for
the first 60 minutes following substance administration. The top
graph compares papaverine's effects on movement alone to
papaverine's effects on amphetamine-induced movement. The bottom
graph compares papaverine's effects on movement alone to
papaverine's effects on PCP-induced movement. Amphetamine was
administered at 1 mg/kg, i.p. PCP was administered at 3.2 mg/kg,
i.p. Papaverine was co-administered with either agent at a dose of
32 mg/kg, i.p. Data represents the mean .+-.SEM crossovers for the
first 60 min following drug administration for n-=8 rats/group.
[0036] ** p<0.01 versus vehicle/vehicle control; * p<0.05
versus vehicle/PCP by Students t-test
DETAILED DESCRIPTION OF THE INVENTION
[0037] PDEs 2, 3 and 5, isozymes, including human PDEs, can, for
example, be prepared from corpus cavernosum; PDE1, isozymes
including human, from cardiac ventricle; and PDE4, isozymes,
including human, from skeletal muscle. PDE6 can be prepared, for
example, from canine retina. Description of enzyme preparation from
native tissue is described, for example, by Boolell, M. et al.,
Int. J. Impotence Research 8:7-52, 1996, incorporated herein by
reference.
[0038] PDEs 7-11 can similarly be prepared from native tissue.
Isozymes from the PDEs 7-9 and 11 families can alternatively be
generated from full length human recombinant clones transfected
into, for example, SF9 cells as described in Fisher, D. A., et al.,
Biochem. Biophys. Res. Comm. 246, 570-577, 1998; Soderling, S. H.
et al., PNAS 96: 7071-7076, 1999; Fisher, D. A. et al., J. Biol.
Chem. 273, 15559-15564, 1998b; and Fawcett, L., et al., PNAS 97:
3702-3707, 2000; respectively. PDE10 can also be generated from a
rat recombinant clone transfected into SF9 cells (Fujishige et al.,
European Journal of Biochemistry, Vol. 266, 1118-1127 (1999)). The
enzymes are then prepared by FPLC from the soluble fraction of cell
lysates as described for PDE6. The aforementioned references are
incorporated in their entireties herein by reference.
[0039] In one assay, a substance is screened for inhibition of
cyclic nucleotide hydrolysis by the PDE10 and the PDEs from the
other gene families. The cyclic nucleotide substrate concentration
used in the assay of each individual PDE is 1/3 of the K.sub.m
concentration, allowing for comparisons of IC.sub.50 values across
the different enzymes. PDE activity is measured using a
Scintillation Proximity Assay (SPA)-based method as previously
described (Fawcett et al., 2000). The effect of PDE inhibitors is
determined by assaying a fixed amount of enzyme (PDEs 1-11) in the
presence of varying substance concentrations and low substrate,
such that the IC.sub.50 approximates the K.sub.i (cGMP or cAMP in a
3:1 ratio unlabelled to [.sup.3H]-labeled at a concentration of
{fraction (1/3 )} K.sub.m). The final assay volume is made up to
100 .mu.l with assay buffer [20 mM Tris-HCl pH 7.4, 5 mM
MgCl.sub.2, 1 mg/ml bovine serum albumin]. Reactions are initiated
with enzyme, incubated for 30-60 min at 30.degree. C. to give
<30% substrate turnover and terminated with 50 .mu.l yttrium
silicate SPA beads (Amersham) (containing 3 mM of the respective
unlabelled cyclic nucleotide for PDEs 9 and 11). Plates are
re-sealed and shaken for 20 min, after which the beads were allowed
to settle for 30 min in the dark and then counted on a TopCount
plate reader (Packard, Meriden, Conn.). Radioactivity units can be
converted to percent activity of an uninhibited control (100%),
plotted against inhibitor concentration and inhibitor IC.sub.50
values can be obtained using the `Fit Curve` Microsoft Excel
extension.
[0040] One example of a selective PDE10 inhibitor is papaverine
(1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline).
Papaverine is a known effective smooth muscle relaxant used in the
treatment of cerebral and coronary vasospasm as well as for
erectile dysfunction. Although the basis of these therapeutic
activities is not well understood, they are generally ascribed to
papaverine's activity as a nonselective phosphodiesterase inhibitor
(The Pharmacological Basis of Therapeutics; Sixth Edition; A. G.
Gilman, L. S. Goodman, A. Gilman (eds.) Macmillan Publishing Co.,
New York, 1980, p. 830). Although papaverine is a naturally
occurring plant alkaloid, its complete biosynthesis has been
described, for example in Brochmann-Hanssen et al., J. Pharm. Sci.
60:1672, 1971, which is incorporated herein by reference.
[0041] A selective PDE10 inhibitor may be administered according to
the present invention either alone or in combination with
pharmaceutically acceptable carriers, in either single or multiple
doses. Suitable pharmaceutical carriers include inert solid
diluents or fillers, sterile aqueous solutions and various organic
solvents. The pharmaceutical compositions formed thereby can then
be readily administered in a variety of dosage forms such as
tablets, powders, lozenges, syrups, injectable solutions and the
like. These pharmaceutical compositions can, if desired, contain
additional ingredients such as flavorings, binders, excipients and
the like. Thus, for purposes of oral administration, tablets
containing various excipients such as sodium citrate, calcium
carbonate and calcium phosphate may be employed along with various
disintegrants such as starch, methylcellulose, alginic acid and
certain complex silicates, together with binding agents such as
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often useful for tabletting purposes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard filled gelatin capsules. Preferred materials for this
include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are
desired for oral administration, the essential active ingredient
therein may be combined with various sweetening or flavoring
agents, coloring matter or dyes and, if desired, emulsifying or
suspending agents, together with diluents such as water, ethanol,
propylene glycol, glycerin and combinations thereof.
[0042] For parenteral administration, solutions containing a
selective PDE10 inhibitor in sesame or peanut oil, aqueous
propylene glycol, or in sterile aqueous solution may be employed.
Such aqueous solutions should be suitably buffered if necessary and
the liquid diluent first rendered isotonic with sufficient saline
or glucose. These particular aqueous solutions are especially
suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal administration. The sterile aqueous media employed
are all readily available by standard techniques known to those
skilled in the art.
[0043] A selective PDE10 inhibitor can be administered in the
therapeutic methods of the invention orally, transdermally (e.g.,
through the use of a patch), parenterally (e.g. intravenously),
rectally, or topically. In general, the daily dosage of PDE10
inhibitor for treating a disorder or condition according to the
methods described herein will generally range from about 0.01 to
about 100 mg/kg body weight of the patient to be treated. As an
example, a selective PDE10 inhibitor can be administered for
treatment of, for example, a psychotic disorder, to an adult human
of average weight (about 70 kg) in a dose ranging from about 1 mg
up to about 7000 mg per day, preferably from about 1 mg to about
1000 mg per day, in single or divided (i.e., multiple) portions.
Variations based on the aforementioned dosage ranges may be made by
a physician of ordinary skill taking into account known
considerations such as the weight, age, and condition of the person
being treated, the severity of the affliction, and the particular
route of administration chosen.
[0044] The following Examples illustrate the present invention. It
is to be understood, however, that the invention, as fully
described herein and as recited in the claims, is not intended to
be limited by the details of the following Examples.
EXAMPLES
Example 1
Selective PDE10 Inhibitors: Papaverine
[0045] Papaverine was screened for inhibition of cyclic nucleotide
hydrolysis by PDE10 and a battery of PDEs from the other gene
families. The cyclic nucleotides substrate concentration used in
the assay of each individual PDE was 1/3 of the Km concentration.
This allows for comparisons of IC.sub.50 values across the
different enzymes.
[0046] PDE activity was measured using the assay with yttrium
silicate SPA beads described above in the Detailed Description
section. Radioactivity units were converted to percent activity of
an uninhibited control (100%), plotted against inhibitor
concentration and inhibitor IC.sub.50 values obtained using the
`Fit Curve` Microsoft Excel extension.
[0047] We observed that papaverine was an exceptionally potent,
competitive inhibitor of PDE10 with an IC.sub.50 value of 18 nM
(Table 1). Papaverine was considerably less potent against all
other PDEs tested. After PDE10, the enzyme inhibited most potently
by papaverine was PDE4D with an IC.sub.50 of 320 nM, a value
19-fold lower than that for PDE10. Thus, these data reveal for the
first time that papaverine is a selective PDE10 inhibitor and that
this compound can be used in studies of this enzyme's
physiology.
1TABLE 1 IC.sub.50 values for papaverine inhibition of the listed
PDEs. IC.sub.50s were determined for each enzyme at a substrate
concentration of 1/3 the Km value to allow for comparisons across
enzymes. The PDE10 selectivity ratio is the IC.sub.50 value for a
given PDE divided by the IC.sub.50 value for PDE10. Selectivity
Ratio Isozyme IC.sub.50, .mu.M (IC.sub.50/IC.sub.50, PDE10) PDE10
0.018 -- PDE1 37 2,055 PDE2 9 500 PDE3A 1.3 72 PDE4A 1.9 105 PDE4B
1.4 78 PDE4C 0.8 44 PDE4D 0.32 18 PDE5 8 444 PDE6 0.86 48 PDE7 27
1,500 PDE8 >10 >555 PDE9 400 20,000 PDE11 11 611
Example 2
Effects of a Selective PDE10 Inhibitor on Cyclic Nucleotide
Metabolism in Medium Spiny Neurons:
[0048] We examined the effects of papaverine, a selective PDE10
inhibitor as determined in Example 1, on cyclic nucleotide
metabolism in rat medium spiny neurons in primary culture. Neurons
cultured from E17 rat embryo striatum in the presence of BDNF
displayed a phenotype very similar to that described previously
(Ventimiglia et al., Eur. J. Neurosci. 7 (1995) 213-222).
Approximately 50% of these neurons stain positive for GABA
immunoreactivity confirming the presence of medium spiny neurons in
the cultures. Expression of PDE-10 message in these cultures at 5
DIV was confirmed by RNAase protection assay.
[0049] The striatal cultures were prepared as previously described
(Ventimiglia et al., Eur. J. Neurosci. 7: 213-222, 1995). Briefly,
striata (caudate nucleus and putamen) are dissected from E17 rats,
were dissociated to produce a single cell suspension and plated at
a density of 5.times.10.sup.4 neurons/well in multiwell plates
coated with poly-L-ornithine/laminin. The cells were plated in
Neurobasal medium with B27 supplements and BDNF (100 ng/mL).
Experiments were typically performed after 4 days in vitro. Medium
spiny neurons comprise the majority of cells in these cultures (50
to 60%, as confirmed by GABA immunoreactivity).
[0050] For the RNAse protection assay, RNA was prepared from these
primary cultures of rat medium spiny neurons by centrifugation at
150,000.times. g at 20.degree. C. for 21 hr through a 5.7 M cesium
chloride gradient as previously described (Iredale, Pa., et al.,
Mol. Pharmacol.50: 1103-1110, 1996). The RNA pellet was resuspended
in 0.3 M sodium acetate, pH 5.2, precipitated in ethanol and the
concentration determined by spectrophotometry. The PDE1O riboprobe
was prepared by PCR amplification of a 914 bp fragment isolated
from mouse cDNA (corresponding to bp 380-bp 1294). This fragment
was then cloned into pGEM3Zf. The vector was linearized and T7 RNA
polymerase was used to synthesize [.sup.32P]-labeled antisense
riboprobe. The RNase protection assay was performed using the RPAII
kit (Ambion). Briefly, 5 .mu.g of total cellular RNA was hybridized
with [.sup.32P]-labeled PDE10 riboprobe (.about.105 cpm/sample)
overnight at 42.degree. C. The following day the samples were
incubated with RNase A and T1 for 30 min at 37.degree. C. and the
protected double-stranded RNA fragments were then precipitated and
run on a 6% polyacrylamide gel containing urea.
[0051] For analyzing effects of papaverine on cyclic nucleotides,
the striatal cell cultures, after four days in vitro, were washed
with Ca.sup.2+/Mg.sup.+ free phosphate buffered saline and
preincubated for an hour in a buffer containing Ca.sup.2+/Mg.sup.+
free phosphate buffered saline, 30 mM HEPES, CaCl.sub.21 mM,
dextrose 1 mg/mL, and MgCl.sub.2 5 mM. The striatal cells were
exposed to phosphodiesterase inhibitors and incubated for twenty
minutes at 37 degrees Celsius. When measuring cGMP, the neurons
were stimulated with sodium nitroprusside, a nitric oxide source
for two minutes following the 20-minute incubation with compound.
When measuring cAMP, the neurons were stimulated with forskolin, an
activator of adenylate cyclase for the duration of the twenty
minute compound incubation. The cells were lysed using a 9:1
combination of cAMP SPA direct screening Assay Buffer (0.05M
acetate with 0.01% sodium azide) and Buffer A (133 mg/mL
dodecyltrimethylammonium bromide) and the lysates were frozen on
dry ice. A cGMP [I125] or cAMP [I125] scintillation proximity assay
(SPA) system (Amersham code RPA 540 and RPA 559, respectively) was
used to detect the concentration of the respective cyclic
nucleotide in the cell lysate.
[0052] Papaverine alone did not effect the low basal level of
either cAMP or cGMP in the striatal cultures. We therefore examined
the effects of the compound under conditions in which cAMP or cGMP
synthesis was stimulated with forskolin or the NO donor sodium
nitroprusside (SNP), respectively. Stimulation of the cultures with
forskolin (0.1-10 .mu.M) for 20 min resulted in a
concentration-dependent increase in cAMP levels. Similarly, brief
exposure of the cultures to SNP (3-1000 .mu.M) for 2 min resulted
in a concentration-dependent increase in cGMP levels. Forskolin
alone (10 M) did not alter cGMP concentrations nor did SNP (300
.mu.M) increase cAMP levels. In order to determine the effects of
papaverine on cAMP and cGMP metabolism, striatal cultures were
incubated with various concentrations of the compound and then
stimulated with submaximally effective concentrations of either
forskolin (1 .mu.M) or SNP (100 .mu.M). These concentrations of
forskolin or SNP caused a 2-3 fold increase over basal in cAMP and
cGMP, respectively. Papaverine caused a concentration-dependent
increase in SNP-induced cGMP accumulation with an EC.sub.200
(concentration of the inhibitor yielding a 2-fold increase) value
of 11.7 .mu.M (Table 2). A maximal effect was observed at 100
.mu.M, at which cGMP levels were elevated 5-fold over that in
cultures stimulated with SNP alone. Papaverine also caused an
increase in cAMP accumulation in forskolin-stimulated cultures.
However, the compound was 3.3-fold less potent at promoting an
increase in cAMP than for cGMP. The effects of papaverine in the
striatal cultures were compared to other PDE inhibitors with
different selectivities (Table 2). IBMX, a nonselective inhibitor
caused a concentration dependent (3-100 .mu.M) increase in both
cGMP and cAMP accumulation in SNP- or forskolin-stimulated cultures
with EC.sub.200 values of 19 and 30 .mu.M, respectively. The
selective PDE4 inhibitor rolipram increased forskolin stimulated
cAMP accumulation with an EC.sub.200 value of 2.5 .mu.M and
required 10-fold higher concentrations to double the rate of cGMP
accumulation. Zaprinast, an inhibitor of cGMP preferring PDEs,
doubled the cAMP levels in these neurons at a concentration of 98
.mu.M. However, 100 .mu.M of this compound did not quite double the
level of cGMP. These data reveal for the first time that papaverine
has a unique effect on cyclic nucleotide regulation in medium spiny
neurons and that this effect is due to the selectivity for
PDE10.
2TABLE 2 EC.sub.200 values for the elevation of cGMP or cAMP in
primary cultures of rat striatal neurons. The EC.sub.200 values
refer to the concentration producing a 200% increase in cGMP or
cAMP in SNP- or forskolin-stimulated cultures, respectively. Each
value is the mean .+-. S.E.M. from the indicated number of
experiments (n). In each experiment, each condition was replicated
in 3-6 sister cultures. ED.sub.200 in .mu.M, .+-. S.E.M. (n)
Compound cGMP cAMP cAMP/cGMP Papaverine 11.7 .+-. 8.2 (4) 38.3 .+-.
11.4 (4) 3.3 Rolipram 29.2 .+-. 10.3 (3) 2.5 .+-. 2.0 (3) 0.09
Zaprinast 98.3 .+-. 10.3 (3) >100 (3) 1 IBMX 19.5 (1) 30.2 (2)
1.5
Example 3
Effect of A Selective PDE 10 Inhibitor in Animal Model of Basal
Ganglia Function
[0053] Studies in human and non-human mammals indicate that the
basal ganglia regulate a range of motor as well as cognition and
emotional/appetitive behaviors (Graybiel, A. M. Current Biology 10
(14):R509-11, 2000). Experimental models in rodents have been
developed which can be used to assess the effects of compounds on
basal ganglia function. We find that papaverine has an
unanticipated unique profile of behavioral effects in two such
models.
[0054] The effect of papaverine alone and in combination with
haloperidol was tested for the ability to induce catalepsy in male
CD rats. This animal model is used to analyze the effects of
compounds on basal ganglia output. Papaverine (1.0, 3.2, 10, or 32
mg/kg.) or vehicle was administered subcutaneously. For some
experiments, this was immediately followed by 1.0 mg/kg haloperidol
(s.c. in 0.3% tartaric acid). Thirty minutes after drug
administration(s), the degree of catalepsy was quantified by
placing the animals forepaws on an elevated (10 cm) bar (1 cm
diameter) and determining the latency to remove both forepaws from
the bar with a latency cutoff of 30 sec. Latencies were ranked
within each treatment group for comparison by a Kruskall-Wallace
analysis of variance. Post hoc analysis was by the Mann Whitney U
test.
[0055] The antipsychotic agent haloperidol produces robust
catalepsy in this model, as previously described (Chartoff, E et
al., J Pharmacol. Exp. Ther. 291:531-537, 1999). A maximally
effective dose of haloperidol was found to be 1 mg/kg, s.c. In
contrast, papaverine did not induce catalepsy when administered
alone at a dose of up to 32 mg/kg s.c. (p=0.86). However as shown
in FIG. 1, papaverine potentiated the cataleptic effect of a
submaximal (0.32 mg/kg, s.c.) dose of haloperidol (p<0.001). The
minimum effective dose of papaverine for potentiation of
haloperidol-induced catalepsy is 3.2 mg/kg, s.c. This experiment
demonstrated that papaverine can alter basal ganglia output in a
direction consistent with antipsychotic activity.
Example 4
Effect of a Selective PDE 10 Inhibitor in Animal Model for
Psychosis
[0056] We next examined the effect of papaverine on locomotor
activity in rats as measured in a shuttle box. Reduction of
PCP-stimulated locomotion in rodents is accepted as a primary
screen in the search for novel antipsychotic agents. Newer a
typical antipsychotic agents generally demonstrate a preferential
inhibition of PCP- versus amphetamine-stimulated locomotor
activity. Adult, male, Sprague-Dawley rats (250-300 g) were
obtained from Charles River (Wilmington, Mass.). Locomotor activity
was assessed using crossover behavior in commercially available
shuttle boxes (Coulbourn Instruments, Allentown, Pa.). Data was
collected in 5 minute intervals for 1 hour after drug
administration. Animals received either vehicle (5% DMSO, 5%
Emulphor, 90% Saline) phencyclidine (PCP, Sigma Chem. Co.) or
amphetamine Sulfate (RBI) followed immediately by either vehicle or
test compound. Statistical analysis was performed using the
Student's t-test.
[0057] The psychostimulants amphetamine and phencyclidine (PCP)
both produce a robust increase in locomotor activity in this model.
Papaverine alone (32 mg/kg, i.p.) produced a small decrease in
locomotor activity which was statistically significant in some
studies (FIG. 2). However, this same dose of papaverine produced a
significant reduction in the locomotor activity stimulated by 3.2
mg/kg, i.p. phencyclidine without effecting that produced by a
behaviorally equivalent dose of amphetamine (1 mg/kg, i.p.).
[0058] Discussion As noted above, a high expression of PDE10 mRNA
in striatum, nucleus accumbens, and olfactory tubercle using in
situ hybridization has already been reported (Seeger, T. F. Et al.,
supra). We have also found using monoclonal antibody for PDE10
protein, a correspondingly high level of PDE10 protein in these
brain regions. Within the striatum and n. accumbens, we found PDE10
mRNA expressed at high levels in the medium spiny neurons. Medium
spiny neurons are the output neurons of the striatum, n. accumbens,
and olfactory tubercle; and represent approximately 95% of all the
neurons in these brain structures. Furthermore, a high level of
PDE10 protein was observed in the projections (axons and terminals)
of medium spiny neurons projecting from the striatum, n. accumbens,
and olfactory tubercle into other brain regions, including the
globus pallidus and substantia nigra. These latter brain regions
themselves have low or undetectable levels of PDE10 mRNA.
Therefore, the high level of PDE10 protein in these regions arises
from the axons and terminals of the medium spiny neurons. In
addition, our studies demonstrated PDE10 mRNA and protein expressed
at lower levels in neurons of other brain regions, namely the
cortex, hippocampus and cerebellum.
[0059] The high levels of PDE10 expression in the striatum and
nucleus accumbens are particularly interesting given that these are
the major cortical input nuclei of the basal ganglia as well as the
principal terminal fields for the midbrain dopaminergic
projections. The striatum and its ventral extension, the nucleus
accumbens, receive glutamatergic afferents from virtually every
region of the cerebral cortex and function as a subcortical
integration site for a wide range of cortical activities. The
dorsal striatum is generally considered to be involved in the
regulation of motor behavior whereas the ventral regions, including
the accumbens, function in the regulation of emotional/appetitive
behaviors. Thus, we believe that PDE10 is likely to be involved in
signaling pathways that regulate a number of these basic
physiological processes.
[0060] Cortical input to the striatum provides the primary
excitatory drive for the GABAergic medium spiny projection neurons
(MSN) which make up 95% of all striatal neurons. Glutamatergic
activation of the MSN is in turn regulated by the massive
dopaminergic input from the midbrain. The antagonistic nature of
these two afferent systems has been demonstrated in numerous
studies. For example, locomotor stimulant activity in laboratory
animals can be produced by either dopamine receptor agonists or
antagonists of the NMDA subtype of the glutamate receptor
(Carlsson, M. L. and Carlsson, A. Trends Neurosci.13:272-276,
1990). The cataleptic effect of D.sub.2 dopamine receptor
antagonists such as haloperidol is reduced by NMDA receptor
antagonists as is haloperidol-induced gene expression (Chartoff, E
et al., J Pharmacol. Exp. Ther. 291:531-537, 1999). More recently,
it has been demonstrated that the blockade of D.sub.2 dopamine
receptors results in an increase in the phosphorylated or activated
state of striatal NMDA receptors (Leveque et al., Journal of
Neuroscience 20(11):4011-4020, 2000).
[0061] The recognition that all clinically effective antipsychotics
possess potent D.sub.2 antagonist activity lead to the original
hypothesis that the symptoms of schizophrenia are the result of
excessive activity in the mesolimbic dopamine system. The ability
of a chemical compound to reduce the stimulant properties of direct
or indirect dopamine agonists became an important laboratory test
in the search for new antipsychotic agents. More recently, the
ability of NMDA receptor antagonist such as PCP to faithfully
reproduced the positive, negative and cognitive symptoms of
schizophrenia in man (Luby et al., 1959; Rosenbaum et al., 1959;
Krystal et al. 1994) has lead to the development of the
hypofrontality theory of schizophrenia. Simply put, this hypothesis
proposes that striatally-mediated behavioral inhibition is
deficient in schizophrenia as a consequence of reduced
glutamatergic and specifically, NMDA receptor-mediated,
neurotransmission. This hypothesis is entirely consistent with the
known antipsychotic effect of D.sub.2 dopamine receptor antagonists
given their ability to disinhibit directly or indirectly cortical
input to the striatum (as described above). The fidelity with which
PCP replicates the symptoms of schizophrenia in humans has lead to
the use of PCP-stimulated locomotion in rodents as a primary screen
in the search for novel antipsychotic agents. The demonstration
that newer and presumably more efficacious a typical antipsychotic
agents demonstrate preferential activity against PCP- over
amphetamine-stimulated locomotor activity would appear to supports
this approach (Gleason S. D. and Shannon H. E. Psychopharmacol.
129:79-84, 1997).
[0062] Although current approaches to antipsychotic therapy
generally target membrane receptors, we propose here that
intracellular manipulations of PDE10 which will enhance NMDA
receptor or reduce dopamine D.sub.2 receptor effects within the MSN
also can produce antipsychotic effects. Increases in cAMP and PKA
activity are known to enhance the response of striatal neurons to
glutamate agonists including NMDA (Colwell, C. S. and M. S. Levine,
J Neuroscience 15(3)1704-1713, 1995). The neuroleptic action of
haloperidol is also dependent on increases in cAMP levels (Ward, R.
P. and D. M. Dorsa, Neuroscience 89(3):927-938, 1999) and PKA
activation (Adams, M. R. et al., Proc Natl Acad Sci USA
94:12157-12161, 1997). Striatal cGMP levels are also increased
after D.sub.2 receptor blockade (Altar, C. A. et al., Eur J.
Pharmacol. 181:17-21, 1990), and PKG is known to phosphorylate some
of the same downstream substrates as PKA, including the endogenous
inhibitor of protein phosphatase I, DARP (Greengard P et al., Brain
Res. Rev. 26:274-284, 1998). Therefore, we hypothesized that agents
able to selectively increase cyclic nucleotide levels in MSN in the
striatum could reasonably be expected to augment striatal function
with a resulting antipsychotic effect, and that a PDE10 inhibitor
will have therapeutic efficacy in the treatment of psychosis
because such a compound will inhibit the PDE10 catalyzed metabolism
of cAMP and cGMP, increasing the levels of these cyclic nucleotides
in the MSNs.
[0063] The experiments with papaverine described above reveal that
a selective PDE10 inhibitor can increase cyclic nucleotide
concentrations in the MSNs in the striatum of the basal ganglia.
The studies in animal models described above show that a selective
PDE 10 inhbitor can produce unique and unexpected alterations in
basal ganglia function.
[0064] In addition to psychosis, abnormal function of the basal
ganglia has been implicated in a variety of neuropsychiatric
conditions including attention-deficit/hyperactivity disorder
(ADHD) and related attentional disorders (Seeman, P. et al.,
Molecular Psychiatry 3:386-96, 1998), depression (Kapur, S., Biol.
Psychiatry 32:1-17, 1992; Willner, P., Brain Res. 287:225-236,
1983) and substance abuse (Self, D. W. Annals of Med. 30:379-389,
1998). Several neurological disorders including Parkinson's
disease, restless leg syndrome (Hening, W. et al., Sleep
22:970-999, 1999) and Huntington's disease are also linked to basal
ganglia dysfunction. Thus, based on our studies described herein,
we believe that a PDE10 inhibitor will have a therapeutic impact on
such disorders.
[0065] As disclosed above, we have found PDE10 mRNA and protein
expressed also in neurons of the hippocampus and cortex. Since
cognitive processes are dependant on hippocampus and cortex
functioning, we believe that PDE10 also plays a role in cognitive
processes and that a PDE10 inhibitor may be used to treat disorders
having a characteristic component of deficient cognitive function,
such as Alzheimer's disease and age-related cognitive decline
(ARCD).
* * * * *